Approximately one in 5 people diagnosed with breast cancer have human epidermal growth factor receptor 2 (HER2-) positive breast cancer. HER2, a gene mutation that causes cell to produce too much of the HER2 protein, tells cells how to grow and divide. The results is that these cells may grow faster, behave aggressively, and ultimately may cause HER2+ breast cancer.[1]

HER2+ metastatic breast cancer (mBC), a subtype of breast cancer with an overexpression and/or amplification of HER2, is a clinically aggressive subtype with poor survival outcomes. The disease, associated with an increased risk for the development of systemic and brain metastases and poor overall survival, remains incurable, driving the ongoing clinical unmet need to develop new HER2-targeted therapies, including chemotherapy-free regimens. [1][2]

Today, the combination of trastuzumab (Herceptin®; Genentech/Roche), pertuzumab (Perjeta®; Genentech/Roche) and a taxane remains the preferred first-line therapy in most treatment scenarios, while after disease progression, the standard of care is trastuzumab emtansine. But treatment options for patients who’s disease have progresses on these agents are more limited.

Over the last decade, promising new agents have emerged offering effective treatment options.  These novel treatment options, including tucatinib and trastuzumab deruxtecan, were recently approved by the US Food and Drug Administration. However, finding the best treatment sequencing, including the best combination treatment option for each individual patient, remains challenging. In addition, there is an unmet need in developing reliable predictive biomarkers, and a better understanding of the mechanisms of resistance to these drugs to maximize patient outcomes and health related Quality of Life (hrQoL).

Approximately 50% of HER2+ breast cancer is also positive for the estrogen receptor (ER+)4. Signaling through HER2 and ER, along with cyclin D-CDK4 kinase, contributes to tumor growth and resistance to therapy. Targeting all 3 pathways may be of benefit to patients.

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A novel treatment combination
A new treatment combination including zanidatamab, an investigational HER2-targeted bispecific antibody targeting 2 non-overlapping extracellular domains (ECD4 and ECD2) on HER2 (known as biparatopic binding), in combination with palbociclib, a CDK4/6 inhibitor, and fulvestrant, a selective estrogen receptor degrader, shows benefit in the treatment of patients with heavily pretreated HER2-positive hormone-receptor positive metastatic breast cancer.

Zanidatamab, which is being developed Zymeworks based on the company’s Azymetric™ platform. The unique design of the drug results in multiple mechanisms of action including dual HER2 signal blockade, increased binding and removal of HER2 protein from the cell surface, and potent effector function leading to encouraging anti-tumor activity in patients.

Encouraging anti-tumor activity
In preclinical and clinical development Zanidatamab has shown encouraging anti-tumor activity with amanageable safety profile in patients with HER2+ mBC as both a monotherapy [3] and in combinations [4]

Data presented at the during a spotlight poster session the San Antonio Breast Cancer Symposium (SABCS) taking place December 6 – 10, 2022 in San Antonio, Tx, shows an overall confirmed objective response rate (cORR) of 33%, disease control rate (DCR) of 92%, and median progression-free survival (mPFS) of 9.6 months. [5]

These results are from the ZWI-ZW25-202 trial (NCT04224272), an ongoing single-arm, open-label, international (Canada, Spain & USA), Phase 2 study. The study included 45 patients with heavily pretreated HER2-positive HR-positive metastatic breast cancer who received zanidatamab in combination with palbociclib and fulvestrant. These participating patients had received prior regimens containing HER2-targeted agents including trastuzumab (100%), pertuzumab (80%), trastuzuman emtansine (98%), and other available treatment options.[5]

In 36 efficacy-evaluable patients, treatment with zanidatamab in combination with palbociclib and fulvestrant resulted in a cORR of 33% and DCR of 92%, and the majority of patients experienced a decrease in tumor size. The mPFS was 9.6 months with seven patients still on study at the time of data cutoff (August 31, 2022). The regimen was generally well-tolerated, with the majority of treatment-related adverse events considered mild to moderate in severity (Grade 1 or 2).

An interim analyses of activity and safety data in heavily pretreated patients with advanced/metastatic HER2+ HER+ BC showed encouraging anti-tumor activity, In patients with response evaluable disease, most demonstrated reduction in the size of their target lesions and 33% of participating patients achieved a confirmed response.

Based on the study data zanidatamab in combination with palbociclib plus fulvestrant is well tolerated and shows a manageable safety profile. These results support further investigation of zanidatamab in combination with palbociclib plus fulvestrant, and enrollment in the study is continuing.

“Zanidatamab together with palbociclib and fulvestrant shows encouraging antitumor activity and a manageable tolerability profile in patients with HER2‑positive hormone-receptor positive breast cancer that has progressed after treatment with multiple HER2-targeted agents,” noted Neil Josephson, M.D., Chief Medical Officer at Zymeworks.

“We are encouraged by the durability of disease control and median progression-free survival in this heavily pretreated patient population indicating that this regimen has the potential to be developed as a chemotherapy-free treatment option for these patients,” Josephson said.

Research beyond breast cancer
In addition to ongoing research in breast cancer, Zanidatamab has been granted Breakthrough Therapy designation for biliary tract cancer from the FDA and the CDE in China, as well as two Fast Track designations, one for previously treated or recurrent HER2-positive biliary tract cancer and another for first-line gastroesophageal adenocarcinoma in combination with standard of care chemotherapy.  Zanidatamab also received Orphan Drug designation for the treatment of biliary tract and gastric cancers in the United States and for gastric cancer in the European Union.

“Our team is excited to present this data as it further supports our plans to continue researching zanidatamab as a possible treatment option for patients living with HER2-positive breast tumors. With topline data from our study surrounding zanidatamab’s effectiveness in addressing biliary tract tumors expected before the end of 2022, we hope to share additional positive news surrounding the drug in the weeks to come,” concluded Kenneth Galbraith, Chief Executive Officer of Zymeworks.

Clinical trials
A Study of ZW25 (Zanidatamab) With Palbociclib Plus Fulvestrant in Patients With HER2+/HR+ Advanced Breast Cancer – NCT04224272

Highlights of prescribing Information
Fulvestrant (Faslodex®; AstraZeneca) [Prescribing Information]
Palbociclib (Ibrance®, Pfizer) [Prescribing Information]
Trastuzumab (Herceptin®; Genentech/Roche) [Prescribing Information]
Pertuzumab (Perjeta®; Genentech/Roche) [Prescribing Information]
Tucatinib (Tukysa®; Seagen)[Prescribing Information]
Trastuzumab deruxtecan (T-DXd; Enhertu®; Daiichi Sankyo and AstraZeneca [Prescribing Information]

[1] Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001 Mar 15;344(11):783-92. doi: 10.1056/NEJM200103153441101. PMID: 11248153.
[2] Cronin KA, Harlan LC, Dodd KW, Abrams JS, Ballard-Barbash R. Population-based estimate of the prevalence of HER-2 positive breast cancer tumors for early stage patients in the US. Cancer Invest. 2010 Nov;28(9):963-8. doi: 10.3109/07357907.2010.496759. PMID: 20690807; PMCID: PMC5094051.
[3] Hamilton E, et al. Abstract P5-20-06 Presented at the 2017 San Antonio Breast Cancer Society Symposium (SABCS), December 5-9, 2017; San Antonio, Tx.
[4] Bedard PL, et al. Abstract P2-13-07 Presented at the 2021 San Antonio Breast Cancer Society Symposium (SABCS), December 7-10, 2021; San Antonio, Tx.
[5] Escrivá-de-Romani S, Alba E, Rodríguez-Lescure Á, Hurvitz S, Miguel Cejalvo J, Gion M, Ferrario C, Ruiz Borrego M, Pezo RC, Hamilton E, Webster M, Pluard T, et al. Treatment of HER2-positive (HER2+) hormone-receptor positive (HR+) metastatic breast cancer (mBC) with the novel combination of zanidatamab, palbociclib, and fulvestrant. Poster: PD18-10. Presented at the 2022 San Antonio Breast Cancer Symposium, December 6-10, 2022, San Antonio, Tx. [Download]

Featured image: San Antonio Breast Cancer Symposium (SABCS), held December 6-10, 2022 at the Henry B. Gonzalez Convention Center in San Antonio, TX. Photo courtesy: © 2022 AACR/SABCS MedMeetingImages/Todd Buchanan.


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